1. Field of the Invention
The present invention relates to spherical seed cores, spherical granules comprising said seed cores and a process for production thereof.
2. Description of the Related Art
In many cases, a pharmaceutical preparation is film-coated as a means for control of the delivery of sustained release-pharmaceuticals, for entero-solubilization, and for an improvement of the stability of active ingredients or a masking of the taste thereof. Where granules are film-coated, spherical elementary granules having a uniform particle size are often used, to enhance the yield and to improve the reproducibility of the coating. To produce spherical elementary granules having a uniform particle size, two main approaches are known. The first approach involves a method wherein a mixture of active ingredients and an excipient is kneaded and extruded to form spheres, as disclosed in Japanese Unexamined Patent Publication (Kokai) No. 63-227518. The second approach involves a method wherein spherical seed cores having a generally uniform particle size are coated with active ingredients and an excipient. In the former method, however, it is difficult to obtain small spherical granules having a particle size of not more than 500 .mu.m, and the particle size distribution is broad and the aspect ratio thereof is unsatisfactory.
Therefore, where precise control of the dissolution rate of an active ingredient is desired, the latter method which provides spherical elementary granules having a uniform particle size is often used. In this case, Nonpareil (component: sucrose, or sucrose/starch) is often used as a seed core, as disclosed in Japanese Unexamined Patent Publication (Kokai) No. 61-1614.
Japanese Unexamined Patent Publication (Kokai) No. 61-213201 refers to microcrystalline cellulose spherical granules, which can be used as seed cores for coating, and having a bulk density of at least 0.65 g/ml and an aspect ratio of at least 0.8. Although this publication defines the aspect ratio as a ratio of the length of the short axis to the length of the long axis, it is not clear whether this aspect ratio relates to that of a particular granule or the average of all of the granules.
Japanese Unexamined Patent Publication (Kokai) No. 63-301816 describes and exemplifies the use of spherical seed cores made from microcrystalline cellulose. However, it does not define any characteristics of the seed cores except for a particle distribution range thereof of between 20 and 32 meshes, and does not describe microcrystalline cellulose as a starting material.
These publications do not disclose a water absorption capacity, and do not disclose the friability of the seed cores. There are believed to be important properties for spherical seed cores. Moreover, these publications do not refer to a process for the production of spherical granules comprising coating spherical seed cores with powder containing an active ingredient, using an aqueous binder solution, and spraying an aqueous solution or suspension of a coating agent thereon followed by drying.
In many cases where seed cores are coated with powder containing active ingredients, an organic or aqueous solution of a binder is used as a binder solution. When a coating is applied, a solution of a coating agent in an organic solvent is used. The use of an organic solvent brings problems relating to environmental pollution, cost, residues and the like. Thus, these organic solvents will be gradually replaced by aqueous solutions or suspensions.
Nevertheless, in a process for the preparation of a pharmaceutical wherein seed cores composed of sucrose or sucrose/starch are coated with a powder containing an active ingredient, using a binder aqueous solution, and further coated by spraying an aqueous solution or suspension of a coating agent, certain problems arise. For example, sucrose, which is a main ingredient of the seed cores, is dissolved, the surface of the seed cores becomes tacky, and the seed cores exhibit a high friability. These problems cause disadvantages, such as aggregation of granules, adhesion of granules to a wall of a coating machine, and a lowered yield. Moreover, the resulting granules have a problem in that the dissolution rate of the active ingredient from the granules is lowered with the passage of time. Further, upon administration, since sucrose, a main ingredient of the seed cores, is gradually dissolved. This results in a reduction of the strength of the granules. An intestinal movement may therefore break the coating of the granules. Since this coating is intended to control the dissolution of the active ingredient, a highly undesirable dissolution profile may appear.